This invention relates to novel compositions of matter containing (2R,4S) itraconazole substantially free of its (2S,4R) isomer. These compositions possess potent activity in treating local and systemic fungal, yeast and dermatophyte infections while avoiding adverse effects associated with the administration of the racemic mixture of itraconazole. Adverse effects include, but are not limited to, hepatotoxicity, arrhythmia, nausea, vomiting and hypersensitivity reactions, including urticaria, abdominal pain, headache, dizziness, and elevations in serum liver enzymes. Also disclosed are methods for treating the foregoing infections in a human while avoiding the adverse effects that are associated with the racemic mixture of itraconazole by administering the (2R,4S) isomer of itraconazole to said human.
The active compound of these compositions and methods is a specific subset of optical isomers of itraconazole, which is described by Van Cutsem, Chemotherapy 38 Suppl. 1, 3-11 (1992) and Heeres et al., J. Med. Chem. 27, 894-900 (1984). It is generically claimed in U.S. Pat. No. 4,267,179, but it does not appear to be specifically disclosed therein.
Itraconazole is defined in the USAN and USP Dictionary of Drug Names as 4-[4-[4-[4- [[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl ]methoxy]phenyl]-1-piperazinyl]phenyl]- 2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one or alternatively as (.+-.)-1-sec-butyl-4-[p-[4-[p-[[(2R*,4S*)-2-(2,4-dichlorophenyl)-2-(1H-1,2 ,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phen yl]-.DELTA..sup.2 -1,2,4-triazolin-5-one. The commercially available material is the cis isomer in the dioxolane ring and is represented by the structural formula I: ##STR1## It will be noted that there are three asymmetric carbons in formula I: two in the dioxolane ring and one in the sec-butyl side chain on the triazolone.
The graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are taken from Maehr J. Chem. Ed. 62, 114-120 (1985): solid and broken wedges are used to denote the absolute configuration of a chiral element; wedge outlines and dotted or broken lines denote enantiomerically pure compounds of indeterminate absolute configuration; wavy lines indicate disavowal of any stereochemical implication which the bond it represents could generate; and solid and broken bold lines, as in I, are geometric descriptors indicating the relative configuration shown but specifically denoting racemic character.
There are eight possible isomers of a structure having three asymmetric carbons: (R,R,R), (R,R,S), (R,S,S), (S,S,S), (R,S,R), (S,R,S), (S,R,R) and (S,S,R). Because the commercially available itraconazole is a cis isomer, it comprises a mixture of only those isomers that describe a cis relationship in the dioxolane ring. Adopting the convention that the first denoted chiral center is at C-2 of the dioxolane ring, the second is at C-4 of the dioxolane and the third is in the sec-butyl group, commercial itraconazole is a mixture of (R,S,S), (R,S,R), (S,R,S) and (S,R,R) isomers. Compounds of this invention have the (2R,4S) configuration in the dioxolane rings and will henceforth be referred to as (2R,4S) itraconazole. (2R,4S) Itraconazole may comprise a mixture of two diastereomers: (R,S,S) (II) and (R,S,R) (III). ##STR2## Since the chirality at the sec-butyl carbon is immaterial to the unexpected advantages of the R,S dioxolane configuration disclosed below, the proportion of (R,S,S) to (R,S,R) can range from 100% (R,S,S) to 100% (R,S,R). Furthermore, because (R,S,S) and (R,S,R) are diastereomers, they can be separated on the basis of chemical properties such as solubility and crystallization in achiral media if need be, but there is no need to do so. There are no reports in the literature of the separation of any of the isomers of itraconazole other than cis from trans, i.e. (R,S,S)/(R,S,R)/(S,R,S)/(S,R,R) mixtures from (R,R,R)/(R,R,S)/(S,S,S)/(S,S,R) mixtures. Racemic cis itrazonazole is commercially available as the free base.
Itraconazole is an orally active, broad-spectrum anti-fungal agent. The compound, a triazole derivative structurally related to miconazole and clotrimazole, impairs the synthesis of ergosterol, which is the principal sterol of fungal cell membranes. This presumably results in an increased permeability and leakage of intracellular content. At high concentration, cellular internal organelles involute, peroxisomes increase, and necrotic changes occur.
Following oral administration, itraconazole is slowly absorbed. Peak plasma levels are attained after 15 days of daily administration, and the pharmacokinetic behavior of itraconazole is nonlinear. The compound is eventually metabolized to several inactive metabolites apparently through hepatic mechanisms and in most subjects no metabolites are excreted in the urine [see Hardin et al., Antimicro. Agents and Chemotherapy 32, 1310-1313 (1988)].
The racemic mixture of itraconazole has recently been approved for use as an antifungal agent for blastomycosis and histoplasmosis. The compound is also being investigated for use in aspergillosis, coccidioidomycosis, cryptococcosis, onychomycosis, dermatophyte and candidiasis infections.
Systemic fungal diseases (systemic mycoses) are usually chronic, very slowly developing conditions induced by opportunistic causative fungi which may not normally be pathogenic. However when they enter a host compromised by HIV, ionizing irradiation, corticosteroids, immunosuppressives, etc. or by such conditions as emphysema, bronchiectasis, diabetes mellitus, leukemia, burns and the like, they may become pathogenic. Symptoms in such fungal diseases are generally not intense, and may include fever, chills, anorexia and weight loss, malaise, and depression. Fungal diseases are often confined to typical anatomic distributions, and many involve a primary focus in the lung, with more characteristic manifestations of specific fungal infections when the fungus disseminates from a primary focus. For example, coccidioidomycosis occurs in a primary form as an acute, benign, self-limiting respiratory disease, with progressive disease developing from the primary form as a chronic, often fatal infection of the skin, lymph glands, spleen and liver. Similarly, blastomycosis primarily involves the lungs, and occasionally spreads to the skin. Other infectious diseases such as paracoccidioidomycosis and candidiasis offer a different course, and depending on the etiology may exhibit several forms involving the skin, mucous membranes, lymph nodes, and internal organs. The diagnosis of specific fungal diseases may be made by isolation of the causative fungus from sputum, urine, blood, or the bone marrow, or with prevalent fungus types by evidence of tissue invasion.
Superficial fungal infections are caused by dermatophytes or fungi that involve the outer layers of the skin, hair or nails. The infections may result in a mild inflammation, and cause intermittent remissions and exacerbations of a gradually extending, scaling, raised lesion. Yeast infections including candidiasis, and oral candidiasis (thrush) are usually restricted to the skin, and mucous membranes, and the symptoms vary with the site of infection. Commonly, infections appear as erythematous, often itchy, exudative patches in the axillas, umbilicus, groin, between toes, and on finger-webs. Oral thrush involves an inflamed tongue, or buccal mucosa and presents as white patches of exudate, while chronic mucocutaneous candidiasis is characterized by red, pustular, crusted, thickened lesions on the forehead or nose.
Many of the "conazole" antifungal agents, including itraconazole, share the same adverse effects. These adverse effects include, but are not limited to, nausea, vomiting, anemia, thrombocytosis, hypersensitivity reactions, hepatotoxicity and some central nervous system toxicity. The racemic mixture of itraconazole has been found to cause nausea and vomiting, anorexia, headache, and dizziness. Hepatotoxicity and hypersensitivity reactions including urticaria and elevations in serum liver enzymes are also associated with the administration of the drug. Hepatoxicity is a less common but more serious adverse effect. Indeed, the use of oral conazoles as first line antifungals is usually discouraged because of the potentially serious consequences of the low incidence of hepatotoxicity [See, for example, Lavrijsen et al. Lancet 340, 251-252 (1992)].
We have found evidence in our own studies in isolated guinea pig hearts that the administration of racemic conazoles may be associated with an increased risk of cardiac arrhythmia. Arrhythmia has not been heretofore reported as a side effect of systemic racemic itraconazole, although a particular subtype of arrhythmia, torsades de pointes, has been reported when racemic itraconazole was administered concurrently with terfenadine. The lack of clinical reports of arrhythmia or QT anomalies may simply be a reflection of the fact that there is to date a relatively small subject population.
Thus it would be particularly desirable to find a compound with the advantages of the racemic mixture of itraconazole which would not have the aforementioned disadvantages.